1 Case 1 A 34-year old women came because of abdominal discomfort. Vital sign was stable. Spleen tip was palpable. CBC and bone marrow aspiration and biopsy were done. Chromosome study showed she had t(9;22) and RT-PCR detected b3a2 type BCR- ABL gene rearrangement.
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3 BM aspiration PB smear
4 She started imatinib 400mg/day po. What is the most accurate method to monitor the residual leukemic burden? 1) BM blast % 2) BM Philadelphia chromosome positive cell % 3) RT-PCR 4) Realtime quantitavie PCR 5) FISH
Chr 9 Chr 22 Philadelphia chromosome BCR BCR ABL ABL Imatinib BCR ABL CML
6 RT-PCR FISH t(9;22)(q34;q11.2), 1R1G2F Realtime Quantitative PCR (RQ-PCR)
7 Measuring Responses in CML Hematologic Response Complete (CHR) Normal CBC, no splenomegaly WBC < 10,000, plt < 450,000 Number of Leukemic Cells 10 12 Cytogenetic Response Complete (CCyR): No Ph+ metaphases Partial (PCyR): 1%-35% Ph+ metaphases Minor (mcyr): 36%-65% Ph+ metaphases Molecular Response Major (MMR): Ratio of BCR-ABL to ABL 0.1% on the International Scale (IS) MR 4 : 4-log reduction MR 4.5 : 4.5-log reduction 10 11 10 10 10 9 10 8 10 7 10 6 Not Measured By CyR
Correlation of BM and PB BCR-ABL/ABL by RQ-PCR n = 126 r = 0.965 p < 0.001 PB BCR-ABL/ABL Clin Cancer Res 9:160, 2003
9 Mechanism of Action of Imatinib
Advances in CML Treatment Options Imatinib approved by FDA Front-line approval of Dasatinib allosct Dasatinib approved by FDA Front-line approval of Nilotinib Omacetaxine approved by FDA 1980 s 1990 s 2000 2002 2004 2006 2008 2010 2012 Interferon- Nilotinib approved by FDA 2013 ELN Recommendations: 1st 1 Line : Imatinib, Dasatinib, Nilotinib 2nd 2 Line Line : Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib Bosutinib approved by FDA Ponatinib approved by FDA 10 Baccarani et al. Blood 2013; doi:10.1182/blood-2013-05-501569
11 Logarithmic Reduction of BCR-ABL Transcript
IRIS (Imatinib Randomized Phase III Trial) 8-Year Results 100 80 60 40 20 % 83 81 85 0 CCyR EFS OS
13 Case 1 At 3 months after beginning of imatinib, BCR-ABL transcript level was 4.2% IS. What will you do? 1) Continue current imatinib dose 2) Change to imatinib 800 mg qd 3) Change to nilotinib 400 mg bid 4) Change to dasatinib 140 mg qd 5) Request ABL mutation study
EuropeanLeukemiaNet Guideline 2013 Optimal Warning Failure Baseline NA High risk or CCA*/Ph+, major route NA 3 mo BCR-ABL1 10% and/or Ph+ 35% BCR-ABL1 > 10% and/or Ph+ 36-95% Non-CHR and/or Ph+ > 95% 6 mo BCR-ABL1 < 1% and/or Ph+ 0 BCR-ABL1 1-10% and/or Ph+ 1-35% BCR-ABL1 > 10% and/or Ph+ > 35% 12 mo BCR-ABL1 0.1% BCR-ABL1 > 0.1-1% BCR-ABL1 > 1% and/or Ph+ > 0 Anytime BCR-ABL1 0.1% CCA/Ph ( 7, or 7q ) CHR loss, CCyR loss *CCA, clonal cytogenetic abnormalities Baccarani M, et al, Blood 2013;122:872-84
15 Case 1 At 6 months of imatinib treatment, BM examination demenstrated no Philadelphia chromosome and BCR-ABL transcript level was 0.8% IS. At 18 months after imatinib, BCR-ABL transcript level increased to 5.8% IS and BM Ph chromosome level increased to 20%. What will you do? 1) Recheck RQ-PCR 1 month later 2) Request FISH study for BCR-ABL 3) Request ABL mutation study 4) Continue current imatinib dose 5) Change to imatinib 800mg qd
% Incidence Imatinib Failure 8 7 6 5 7.5 4.8 Failure Loss of CHR, MCyR Progression to AP/BC Death Progression to AP/BC 4 3 3.3 2.8 2 1 0 Year 1.5 1.6 1.5 0.9 0.8 0.5 0.4 1 2 3 4 5 6 0 Hochhaus A. et al, Blood. 2007
Imatinib resistant ABL mutations 1. F317 2. T315 3. F359 4. M244 5. G250 6. Q252 7. Y253 8. E255 9. M351 10. E355 11. V379 12. L387 13. H396
T315I Hydrogen bond Gorre. Science 2001
20 Case 1 As ABL kinase mutation study showed she had Y253H mutation, she started dasatinib 140 mg qd and BCR-ABL transcript level at 3 months was 0.4% IS. At 24 months after dasatinib, she developed dyspnea, cough and pleuritic pain on inspiration. She maintained normal CBC and BCR-ABL transcript level was 0.001% IS. What will you do? 1) Check compliance 2) Try bronchoscopic alveolar lavage 3) Stop dasatinib and start steroid 4) Request ABL mutation study 5) Change to nilotinib
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22 HSCT vs Second G TKI after Imatinib Failure
23 Case 2 27-year old male patient developed sweating and weight loss of 5 kg. He had taking imatinib 400 mg qd for 6 months for CML chronic phase. CBC showed WBC 45,710/mm 3, blast 60%, Hb 9.6 g/dl, PLT 56,000/mm 3. BM aspiration showed 70% blasts with persistent Ph chromosome 12/20(+). What is the best therapeutic option for him? 1) Dasatinib 2) Nilotnib 3) Ponatinib 4) Imatinib + steroid 5) Allogeneic hematopoietic cell transplantation
OS After Progression To AP/BC In The ENESTnd And IRIS Trials Larson RA, et al. Leukemia 26:2197, 2012
25 Blastic Crisis WHO Definition Blast 20% of PB or BM nucleated cells Extramedullary blast proliferation Lorge foci or clusters of blasts in BM Bx Treatment ALL or AML type induction chemotherapy + TKI followed by allogeneic HSCT TKI followed by Allogeneic HSCT Clinical trial